Glucagon-like peptide-1 receptor activation modulates pancreatitis-associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice.

Abstract

OBJECTIVE:

Clinical reports link use of the glucagon-like peptide-1 receptor (GLP-1R) agonists exenatide and liraglutide to pancreatitis. However, whether these agents act on the exocrine pancreas is poorly understood.

RESEARCH DESIGN AND METHODS:

We assessed whether the antidiabetic agents exendin (Ex)-4, liraglutide, the dipeptidyl peptidase-4 inhibitor sitagliptin, or the biguanide metformin were associated with changes in expression of genes associated with the development of experimental pancreatitis. The effects of Ex-4 when administered before or after the initiation of caerulein-induced experimental pancreatitis were determined. The importance of endogenous GLP-1R signaling for gene expression in the exocrine pancreas and the severity of pancreatitis was assessed in Glp1r(-/-) mice.

RESULTS:

Acute administration of Ex-4 increased expression of egr-1 and c-fos in the exocrine pancreas. Administration of Ex-4 or liraglutide for 1 week increased pancreas weight and induced expression of mRNA transcripts encoding the anti-inflammatory proteins pancreatitis-associated protein (PAP) (RegIIIbeta) and RegIIIalpha. Chronic Ex-4 treatment of high-fat-fed mice increased expression of PAP and reduced pancreatic expression of mRNA transcripts encoding for the proinflammatory monocyte chemotactic protein-1, tumor necrosis factor-alpha, and signal transducer and activator of transcription-3. Sitagliptin and metformin did not significantly change pancreatic gene expression profiles. Ex-4 administered before or after caerulein did not modify the severity of experimental pancreatitis, and levels of pancreatic edema and serum amylase were comparable in caerulein-treated Glp1r(-/-) versus Glp1r(+/+) mice.

CONCLUSIONS:

These findings demonstrate that GLP-1 receptor activation increases pancreatic mass and selectively modulates the expression of genes associated with pancreatitis. However, activation or genetic elimination of GLP-1R signaling does not modify the severity of experimental pancreatitis in mice.

• Authors: Jacqueline A Koehler, Laurie L Baggio, Benjamin J Lamont, Safina Ali, Daniel J Drucker
• Journal: Diabetes (Diabetes) Vol. 58 Issue 9 Pg. 2148-61 (Sep 2009) ISSN: 1939-327X [Electronic] United States
• PMID: 19509017 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dietary Fats
• Early Growth Response Protein 1
• Egr1 protein, mouse
• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Pancreatitis-Associated Proteins
• Peptides
• REG3A protein, human
• Receptors, Glucagon
• Venoms
• Liraglutide
• Ceruletide
• Glucagon-Like Peptide 1
• Exenatide

Topics

• Animals
• Ceruletide (toxicity)
• Dietary Fats (pharmacology)
• Disease Models, Animal
• Early Growth Response Protein 1 (genetics)
• Exenatide
• Gene Expression (drug effects, physiology)
• Genes, fos (physiology)
• Glucagon-Like Peptide 1 (analogs & derivatives, metabolism, toxicity)
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents (toxicity)
• Liraglutide
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Pancreas, Exocrine (drug effects, physiology)
• Pancreatitis (chemically induced, metabolism, physiopathology)
• Pancreatitis-Associated Proteins
• Peptides (toxicity)
• Receptors, Glucagon (genetics, metabolism)
• Severity of Illness Index
• Signal Transduction (drug effects, physiology)
• Venoms (toxicity)